It is known that endothelin is a polypeptide composed of 21 amino acid residues, is produced by endothelial cells of human or other mammals, and exhibits a potent vasoconstrictor effect and a prolonged, potent pressor action. It is also known that the production mechanism for endothelin begins with the biosynthesis of preproendothelin, which undergoes processing in the cells to become big endothelin, followed by the hydrolysis of the peptide bond between Trp21-Val22 of big endothelin by endothelin-converting enzyme to produce endothelin. It is further known that endothelin-converting enzyme itself is a phosphoramidon-sensitive neutral metalloprotease (Nature, Vol. 332, p.411-415, 1988; Biochem. Biophys. Res. Commun., Vol. 168, p.1128-1136, 1990; Ibid, Vol. 171, p.1192-1198, 1990; FEBS Letters, Vol. 272, p.166-170, 1990).
As reported, the levels of endothelin are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, atherosclerosis, subarachnoid hemorrhage, disseminated intravascular coagulation, Buerger's disease, Takayasu's disease, Kawasaki's disease, diabetes, or renal failure caused by administration of cisplatin, and also in the washing fluids of respiratory tract or the blood of asthma patients as compared with normal levels (Japan J. Hypertension, Vol. 12, p.79, 1989; J. of Vascular Medicine Biology, Vol. 2, p.207, 1990; J. of Am. Med. Association, Vol. 264, p.2868, 1990; The Lancet, Vol. 2, p.747-748, 1989, Vol. 2, p.1144-1147, 1990; J. of Int. Secr. Association, Vol. 67, p.421, 469-470, 1991).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., i, 73 (1989)) and an improved renal function by the endothelin antibody in an acute renal failure model (J. Clin. Invest., 83, 1762-1767 (1989)), have been reported. Therefore, endothelin is assumed to be one of mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, it has become clear that endothelin is secreted not only by vascular endothelial cells, but also by tracheal epitherial cells or renal parenchymal cells (FEBS Letters, Vol. 255, p.129-132, 1989; FEBS Letters, Vol. 249, p.42-46, 1989).
It has also been discovered that endothelin regulates the release of endogenous physiologically active substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A.sub.2, prostacyclin, noradrenaline, angiotensin II, and substance P (Biochem. Biophys. Res. Commun., Vol. 157, p.1164-1168, 1988; Biochem. Biophys. Res. Commun., Vol. 155, p.167-172, 1989, Proc. Natl. Acad. Sci. USA, Vol. 85, p.9797-9800, 1989; J. of Cardiovasc. Pharmacol., Vol. 13, p.S89-S92, 1989; Japan J. Hypertension, Vol. 12, p.76, 1989; Neuroscience Letters, Vol. 102, p.179-184, 1989). In addition, endothelin also causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, Vol. 247, p.337-340, 1989; Eur. J. Pharmacol., Vol. 154, p.227-228, 1988; Biochem. Biophys. Res. Commun., Vol. 159, p.317-323, 1989).
Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276-279 (1989)).
On the other hand, endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively. These findings suggest that endothelin is one of important mediators for endotoxin-induced diseases (Biochem. Biophys. Res. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
In addition, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PK1 cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.
Therefore, substances which inhibit endothelin-converting enzyme suppress overproduction of endothelin and thus may be considered to be effective in the prevention and treatment of the various diseases mentioned above. Nevertheless, aside from phosphoramidon, there have been no reports to date of any potent inhibitors of endothelin-converting enzyme.
Endothelin is an endogenous physiologically active substance which directly or indirectly (by regulating the liberation of various endogenous substances) causes sustained contraction of vascular or non-vascular smooth muscles. Its overproduction or over-secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Reynaud's disease, Buerger's disease, Takayasu's disease, Kawasaki's disease, diabetes, bronchial asthma, arteriosclerosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. In addition, it is suggested that endothelin serves as an important mediator involved in diseases such as endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, cyclosporin- or cisplatin-induced renal failure or hypertension, congestive heart failure, vascular restenosis, and inflammatory bowel diseases. Thus, an invention of an inhibitor of endothelin-converting enzyme would provide a novel method for the treatment of the various kinds of diseases mentioned above.